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PubMed1992

(Sub)periosteal Ewing's sarcoma of bone.

Ewing's sarcoma is a small malignant round-cell tumour that arises from mesenchymal cells, predominantly in the medullary cavity of bone. In exceptional cases it originates in the soft tissues and subsequently invades the underlying bone. A (sub) periosteal origin of Ewing's sarcoma is a very rare condition: only a few cases have been published so far. Three cases of (sub)periosteal Ewing's sarcoma, having received neoadjuvant chemotherapy and radiation therapy as well as wide excision, are reported.

Adolescent↗
PubMed1997

The impact of intraoperative brachytherapy on surgery of Ewing's sarcoma.

Surgery of Ewing's sarcoma sometimes results in an inadequate surgical margin. The influence of intraoperative brachytherapy on local control of the tumor, operation time, blood loss, and surgical complications was evaluated, comparing the results of 20 patients who received brachytherapy to a series of 42 patients receiving surgery without brachytherapy. The dose of intraoperative brachytherapy ranged between 9 Gy and 21 Gy. The average operation time was longer in 20 cases with brachytherapy (7.9 h) than in 42 cases without brachytherapy (4.3 h) (P < 0.0001). The average blood loss in the groups with (3531 ml) and without brachytherapy (3515 ml) was comparable (P = 0.3840). The surgical complication rate in patients receiving brachytherapy was also similar to that of untreated patients (30% versus 31%, P = 0.7690). Local relapse developed in 1 of 20 patients who received brachytherapy and 1 of 42 patients without brachytherapy. On the basis of this analysis, it can be concluded that this procedure is safe and does not increase of the acute complication rate. The latest results of local controls are awaited.

Adolescent↗
PubMed1994

ERG gene is translocated in an Ewing's sarcoma cell line.

Ewing's sarcoma (ES) and related neoplasias are characterized by the reciprocal translocation, t(11;22)(q24;q12). The translocation has been reported to generate a fusion gene between the EWS (a previously undescribed gene on chromosome 22) and FLI1 genes. We report a similar translocation of EWS and FLI1 in an Askin's tumor cell line (SK-NM-C). Further, we describe an alternative translocation in an ES cell line (#5838) in which the 5' end of the EWS gene is juxtaposed to the 3' end of the ERG gene. The ERG gene is on chromosome 21, but no microscopically visible changes in chromosome 21 were observed. Elevated steady state levels of the EWS/ERG fusion gene transcript were detected in the #5838 cell line. This is the first report of a structural alteration of ERG in human cancer. Also, it confirms a general mechanism of generating putative oncogenic fusion genes by placing an ETS DNA binding domain in direct proximity to the carboxy terminus domain (CTD) related region of the EWS gene.

Base Sequence↗
PubMed2003

Beta-platelet-derived growth factor receptor mediates motility and growth of Ewing's sarcoma cells.

The Ewing's sarcoma family of tumors (ESFT) contain a translocation, t(11;22), which results in the novel oncogenic fusion protein EWS/FLI1. Platelet-derived growth factors (PDGF) and their receptors (PDGFR) are involved in the induction and proliferation of numerous solid tumors and are the potential candidates for novel targeted antitumor therapy. Since a relation was reported between PDGF-C and EWS/FLI1, we sought to characterize the PDGF signaling pathway in ESFT. Eight out of nine ESFT cell lines were found to express significant levels of beta-PDGFR. Interestingly, none of the tested cell lines expressed alpha-PDGFR, which is the receptor isotype required for PDGF-C binding. By immunohistochemical staining 47 of 52 (90.4%) archival tumor samples from patients with ESFT were positive for beta-PDGFR. ESFT cell lines were treated with PDGF-AA or PDGF-BB ligands to evaluate downstream signaling. Autophosphorylation of beta-PDGFR and tyrosine phosphorylation of PLC-gamma, PI3Kp85 and Shc were detected only in PDGF-BB-stimulated cells that express beta-PDGFR. Receptor function was further evaluated using chemotaxis assays that showed TC-32 cell migration towards PDGF-BB. A specific PDGFR kinase inhibitor AG1295 blocked beta-PDGFR activation, downstream signaling, growth in cell culture and chemotaxis of TC-32 cells. AG1295 also delayed tumor formation and prolonged survival in an ESFT animal model. We conclude that ESFT express beta-PDGFR and that this is a functional and potentially crucial signaling pathway. Therefore, beta-PDGFRs may provide a novel therapeutic target in ESFT that can be utilized to design better treatment modalities.

Animals↗
PubMed2003

Rapamycin induces the fusion-type independent downregulation of the EWS/FLI-1 proteins and inhibits Ewing's sarcoma cell proliferation.

Ewing's sarcoma (ES) is the prototype of a family of tumors (ESFT) of neuroectodermal origin formed by small, round cells with limited neural differentiation, which arise most frequently within bones in children or adolescents. The proliferation of ESFT cells is highly dependent on the establishment of, and signaling through several growth factor-mediated autocrine loops. The mammalian target of rapamycin (mTOR) is a central regulator of translation and cell proliferation, involved in the cellular response to various nutritional, stress and mitogenic effectors. As mTOR has recently been associated with certain human cancers, we investigated the possibility that mTOR played a role in the regulation of ES cell proliferation. Results showed that ES cell lines carrying EWS/FLI-1 alleles of different types expressed different levels of total and phosphorylated mTOR protein. We demonstrate that rapamycin, an mTOR inhibitor, efficiently blocked the proliferation of all cell lines by promoting cell cycle arrest at the G1 phase. This was paralleled by the downregulation of the levels of the EWS/FLI-1 proteins, regardless of their fusion type, and the concomitant restoration of the expression of the TGF-beta type 2 receptor (TGFbeta RII), which is known to be repressed by several EWS-ETS fusion proteins. The expression of a rapamycin-resistant mTOR construct prevented both the proliferation blockade and the EWS/FLI-1 downregulation. These data demonstrate that mTOR signaling plays a central role in ES cell pathobiology and strongly suggest that the use of rapamycin as a cytostatic agent may be an efficient tool for the treatment of ES patients.

Alleles↗
PubMed1985

Fractures of long bones previously treated for Ewing's sarcoma.

Patients with Ewing's sarcoma of a long bone who survive for two years from the time of diagnosis and have been treated with irradiation and chemotherapy have a significant risk of fracture of the involved segment of bone. In our experience, this risk is especially high when the humerus or femur is involved. Healing of these fractures is not normal, and our data suggest that early or even prophylactic internal fixation and bone-grafting may be indicated.

Adolescent↗
PubMed1995

[The role of radiotherapy in the local treatment of Ewing's sarcoma].

Therapy of Ewing's sarcoma consists of adequate local treatment for control of the primary tumor (surgery or radiotherapy or a combination of both) and systemic therapy. Tumors with favorable prognosis (small tumor volume, good response to chemotherapy) may be managed by a single local modality. In tumors with poor prognosis, combined local treatment (surgery plus radiotherapy) seems to improve local control and survival. As an innovative approach, preoperative radiotherapy for high-risk tumors is investigated in the EICESS-92-study.

Adolescent↗
PubMed1984

Ewing's sarcoma of mandible.

Ewing's sarcoma is a highly malignant tumour which develops from the medullary tissue of bones. It accounts for four to five per cent of all primary bone tumours (Ackerman et al., 1968; Dahlin, 1978) and usually presents as a solitary lesion in patients below the age of 30 years. It is most commonly situated in a long bone of the upper and lower extremities, pelvis, ribs and vertebrae. We describe the clinico-pathological features and management of a 19 year old male patient who developed Ewing's sarcoma of the mandible, an uncommon site of origin. It is hoped that the improvement in prognosis of this tumour observed in other sites due to aggressive chemotherapy will also pertain for Ewing's sarcoma within the mandible. This case illustrates the difficulties of management at this anatomic site.

Adult↗
PubMed1991

Neuronal differentiation of Ewing's sarcoma induced by cholera toxin B and bromodeoxyuridine--establishment of Ewing's sarcoma cell line and histochemical study.

An Ewing's sarcoma (ES) cell line was established from a metastatic bone marrow specimen in a patient with advanced disease, and some histochemical characteristics were investigated by neuronal differentiation induced with cholera toxin B (CTB) and bromodeoxyuridine (BrdU). Neuronal differentiation was investigated by the expression of neurofilament and Leu-7, and glial differentiation was observed by expression of S-100 protein. Neurofilament (NF) and Leu-7 were positive in ES cells and these were expressed more intensively by induction with CTB than with BrdU. There was no expression of S-100 protein in untreated or differentiated ES cells. ES cells became differentiated to neuronal cells with CTB and BrdU, but it was not observed, that ES cells had the potential to differentiate to glial cells. It appears that ES is of more primitive neural origin than neuroblastoma, primitive neuroectodermal tumors and other related neural tumors.

Antigens, Differentiation↗
PubMed1999

Regulatory role of mevalonate and N-linked glycosylation in proliferation and expression of the EWS/FLI-1 fusion protein in Ewing's sarcoma cells.

The Ewing's sarcoma cell line RD-ES, which carries the EWS/FLI-1 fusion gene, responded to the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor lovastatin with growth arrest. Replenishment of mevalonate (MVA) to the arrested cells restored cell growth. However, if tunicamycin (TM), which is an inhibitor of N-linked glycosylation, was present together with MVA the cells remained arrested, indicating that N-linked glycosylation is of importance for growth of Ewing's sarcoma cells. Inhibition of the biosynthesis of EWS/FLI-1 fusion protein by treatment with antisense oligonucleotides also led to growth arrest, suggesting that this protein is of importance for cell growth. We investigated whether MVA synthesis and N-linked glycosylation could be involved in regulation of the expression of the EWS/FLI-1 fusion protein, which in fact contains four potential sites for N-linked glycosylation. We found that inhibition of both HMG-CoA reductase and N-linked glycosylation drastically decreased the expression of the fusion protein, which mainly appears in the cell nuclei. There was no significant difference in the inhibitory effect on the fusion protein between the cytoplasm and the cell nuclei, indicating that the transport of the fusion protein to the cell nucleus is not affected. The fusion protein did not exhibit any gel electrophoretic mobility shift after treatment of the cells with lovastatin or TM, and it did not incorporate [3H]glucosamine. Therefore we can conclude that the fusion protein is not a glycoprotein. The decreased expression of the fusion protein following lovastatin or TM treatment was found to be due to a lowered stability of de novo-synthesized fusion protein. The down-regulation of the fusion protein was correlated to growth arrest. Furthermore, the kinetics between the expression of EWS/FLI-1 fusion protein and the initiation of DNA synthesis in MVA-stimulated cells were similar. Taken together, our data suggest that the regulatory role of N-linked glycosylation in the expression of the EWS/FLI-1 fusion protein is important for growth of Ewing's sarcoma cells. Possible mechanisms underlying TM-induced decrease in EWS/FLI-1 expression may involve the breaking of growth factor receptor pathways.

Amino Acid Sequence↗
PubMed2000

Ewing's sarcoma.

Patients with Ewing's sarcoma should be transferred to a comprehensive cancer center for evaluation and management when the diagnosis is suspected. Proper biopsy technique is essential to preserve all therapeutic options, including limb preservation surgery. In addition to conventional histologic examination, biopsy tissue must be obtained for molecular biology studies. Demonstration of the consistent chromosomal translocation associated with Ewing's sarcoma is essential for diagnosis, and the specific type of fusion transcript has prognostic implications. Treatment must be intimately coordinated among oncologist, surgeon, and radiation oncologist. Successful treatment requires systemic, multi-agent chemotherapy and local control. The primary tumor can be treated with surgery, radiation therapy, or a combination of the two. The choice of modality should be dictated by the age of the patient, location of the primary tumor, functional consequences of the intervention, and concern about late effects, especially secondary malignancy. Treatment of the patient who presents with clinically detectable metastatic disease or who relapses after initial therapy remains unsatisfactory and controversial.

Antineoplastic Agents↗
PubMed1993

[Therapy of Ewing's sarcoma].

Therapy of Ewing's sarcoma requires a qualified clinical, radiological, and pathohistological diagnosis and, in particular, an optimal therapy by an experienced team of oncological specialists. Important prognostic factors are the presence of hematogenous metastases at diagnosis, the initial tumor volume, the response to chemotherapy, and adequate local therapy. Presently, cure rates of more than 60% can be achieved for localized Ewing's sarcoma by combination of local therapy and chemotherapy. The four-drug combination VACA (vincristine, actinomycin D, cyclophosphamide, adriamycin) can be considered as cytostatic gold standard. More aggressive regimens (VAIA, EVAIA, autologous bone marrow transplant) may be beneficial in subgroups and are under investigation. Concerning local therapy adequate radiotherapy plays a major role and achieves the same survival rates as radical surgery, comparable patient selection provided. Several factors have impact on radiotherapeutic results, especially total dose (45 Gy large volume, 55 Gy to the primary tumor), target volume (safety margin at least 2 cm according to the pretreatment volume, at least 5 cm in proximal and distal extension of long bones), timing of radiotherapy (as early as possible) and quality of treatment. Radiotherapy as sole local treatment is indicated in inoperable lesions (spine, sacrum, skull) and in small, good-responding tumors. High-risk patients should receive combined radiotherapeutic-surgical treatment, preferably as pre-operative irradiation. The value of hyperfractionation is not yet proven despite theoretical advantages.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1987

Small round blue cell sarcoma of bone mimicking atypical Ewing's sarcoma with neuroectodermal features. An analysis of five cases with immunohistochemical and electron microscopic support.

Ewing's sarcoma (ES) of bone may occasionally display rosette-like textures mimicking Homer-Wright ones, as seen in neuroectodermic neoplasms (neuroblastoma, peripheral neuroepithelioma). Of a group of 39 cases of ES, reviewed with electron microscopic study, the authors have isolated five atypical ES, which histologically also possessed neuroectodermic traces. These tumors were composed of small round blue cells with rosette-like figures and cytoplasmic glycogen. The immunohistochemical analysis showed positivity for neuron-specific enolase (NSE) as well as for HNK-1 (leu-7) monoclonal antibody. Electron microscopic examination confirmed the tumor cell as being of small round type, with a dense chromatine pattern and the presence of isolated dendritic processes, as well as synaptic-like buttons; intermediate filaments, neurotubuli, and dense-core neurosecretory granules also were seen. Moreover, in two cases basement-like condensations surrounded some cells. Scanning electron microscopic study in one case confirmed the presence of rosette-like figures and cell elongations with short dendritic projections of the cytoplasm. Clinically and radiologically these cases showed features similar to ES of bone; one case, located in the chest wall, had a local relapse after treatment, with the histologic features of a pleomorphic neuroblastoma. The authors conclude that these tumors resemble closely immature neuroepithelioma of soft tissue but, being primary to bone, are superimposable on those described as "neuroectodermal tumors of bone."

Antibodies, Monoclonal↗
PubMed1997

Ewing's sarcoma and primitive neuroectodermal tumor in adults: are they different from Ewing's sarcoma and primitive neuroectodermal tumor in children?

PURPOSE: To determine whether age at diagnosis influences the behavior of Ewing's sarcoma and primitive neuroectodermal tumor (PNET). PATIENTS AND METHODS: We reviewed the clinical features, treatment, and outcome of 59 consecutive patients with Ewing's sarcoma and PNET treated on the Adult Sarcoma Unit at our institution from 1980 to 1995. RESULTS: The 37 male and 22 female patients had a median age of 24 years. Lower limb was the most common primary tumor site. Fifteen patients had nonmetastatic tumor less than 100-mL volume, 27 had nonmetastatic disease greater than 100-mL volume, and 17 had evidence of metastatic disease at presentation. The origin of the primary tumor was soft tissue in 28 cases, bone in 30, and uncertain in one. The Kaplan-Meier estimate of 5-year overall survival (OS) in all patients was 38% and of progression-free survival (PFS), 27%. When patients with metastatic disease at presentation were excluded, these figures increased to 52% and 34%, respectively. Bulk of disease at presentation and response to primary treatment were statistically highly significant predictors of both PFS and OS. Age and tissue of origin of the tumor did not influence outcome. CONCLUSION: The behavior of Ewing's sarcoma and PNET in adults is no different from its behavior in children. We feel the way forward in the treatment of adults with Ewing's sarcoma and PNET is for them to be included in the current multicenter trials of multidisciplinary treatment directed at children.

Adolescent↗
PubMed1977

Leukocyte migration inhibition in patients with Ewing's sarcoma by 3-M potassium chloride extracts of fresh and tissue-cultured Ewing's sarcomas.

Leukocyte migration inhibition (LMI) assays were performed to detect cell-mediated immune reactions against tumor-associated antigens (TAA) of Ewing's sarcoma. With the use of crude antigen preparations obtained by 3M KCl extractions of fresh Ewing's sarcoma or of tissue culture cells derived from a pleural effusion of a Ewing's sarcoma patient, assays were performed with leukocytes from these patients, patients with other cancers, and normal donors. The results demonstrated approximately 60% or greater positive LMI reactivity in Ewing's sarcoma patients, as compared to less than 10% reactivity of normal donors, with the use of extracts of either fresh or tissue-cultured Ewing's sarcoma cells. A lower proportion of positive reactivity was observed in patients with breast and lung cancer. Further specificity tests indicated that a smaller proportion of patients with Ewing's sarcoma had LMI reactivity with KCl extracts of tissue-cultured cells derived from breast cancer of fresh lung cancer cells than did patients with the homologous disease. The results indicate that many patients with Ewing's sarcoma have cell-mediated immunity toward TAA on Ewing's sarcomas. Inasmuch as all the LMI assay were performed with allogeneic extracts, the data also suggested that different Ewing's sarcomas possess common antigens and that some breast and lung cancers may share some TAA with Ewing's sarcoma.

Antigens, Neoplasm↗
PubMed2004

Ewing's sarcoma and primitive neuroectodermal tumor of hand and forearm. Experience of the Cooperative Ewing's Sarcoma Study Group.

PURPOSE: Because Ewing's sarcoma (EWS) is extremely rare in the hand and forearm, only limited data are available for planning treatment or predicting prognosis. METHODS: Data of 33 patients with EWS of the forearm or hand who were enrolled in studies of the German Association for Paediatric Oncology/Haematology and the European Intergroup Cooperative Ewing's Sarcoma Study Group were analyzed. Patients received neoadjuvant multi-agent chemotherapy according to the valid protocol. Local treatment consisted of surgery (n=7), radiotherapy (n=7), or a combination of both (n=19). RESULTS: The 5/10-year overall survival rate was 84.1% (95% CI: 71.2-96.9)/74.1% (95% CI: 56.8-91.5), and both 5/10-year event-free survival rate were 71.3% (95% CI: 55.4-87.1). Only one of seven patients with secondary metastases was in remission at the time of analysis. One patient with local recurrence and another with primary metastases died. Altogether, eight of 33 patients died of their disease. The event-free survival rate was 80.6% in patients with good response to chemotherapy and 33.3% in patients with poor response. Surgery in combination with radiotherapy achieved a higher survival rate compared with radiotherapy or surgery alone. One out of two patients with non-wide margins of resection died of disease. CONCLUSIONS: The results demonstrate a remarkably high survival rate for patients with EWS of the hand and forearm.

Adolescent↗